A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ 'helper' Tcells (TH) in priming of cytotoxic CD8+ T lymphocytes (CTL) responses in vivo. Whereas CTL mediated via cross-priming depend on the presence of CD4+ T cells, many others, including those against many viruses and bacteria, can apparently proceed in their absence. We have recently demonstrated that in both settings, TH endows CTL with a key characteristic of immune memory; the capacity for 2 degree expansion upon re-exposure to antigen. This finding offers a unifying explanation for previous paradoxical observations of TH-dependent and TH-independent CTL responses and provides a new theoretical framework for understanding how CD8 T cells are regulated by CD4+ T cells. The goal of this research is to define the mechanism through which T help is conferred to CTL and to determine how 'help' influences the functional development of CD8 T cells. Our hypothesis is that TH is transmitted to CD8+ T cells through discrete inductive signals that modify the instructional program guiding CTL development to include the capacity for 2 degree expansion. Our specific goals are therefore I) to identify those aspects of CTL development and function which are "programmed" by TH during priming, II) to define the signals through which the capacity for 2 degree expansion is conferred to "helped" CTL, and III) to define the molecular pathways that lead to the disparate fates of 'helped' versus 'helpless' CTL upon 2 degree stimulation. Our preliminary data indicate that a major component of this latter process involves activation-induced apoptosis mediated via tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL-R2 (DR5) pathway. Our experiments will involve study of the 1 degree and 2 degree responses of endogenous and transgenic/knockout CD8+ T cells at the cellular and molecular level following a variety of in vivo antigenic challenges. We anticipate that this project will allow a clear understanding of the mechanism of T help for CTL and will identify how this process can be strategically manipulated to promote beneficial responses against infectious pathogens as well as inhibiting pathologic autoimmunity.